Co-targeting SOS1 enhances the antitumor effects of KRAS G12C inhibitors by addressing intrinsic and acquired resistance.

Autor: Thatikonda V; Boehringer Ingelheim RCV, Vienna, Austria. vthatikonda@exscientia.co.uk.; Exscientia, Vienna, Austria. vthatikonda@exscientia.co.uk., Lyu H; Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Jurado S; Boehringer Ingelheim RCV, Vienna, Austria., Kostyrko K; Boehringer Ingelheim RCV, Vienna, Austria., Bristow CA; Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Albrecht C; Boehringer Ingelheim RCV, Vienna, Austria., Alpar D; Boehringer Ingelheim RCV, Vienna, Austria., Arnhof H; Boehringer Ingelheim RCV, Vienna, Austria., Bergner O; Boehringer Ingelheim RCV, Vienna, Austria., Bosch K; Boehringer Ingelheim RCV, Vienna, Austria., Feng N; Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Gao S; Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Gerlach D; Boehringer Ingelheim RCV, Vienna, Austria., Gmachl M; Boehringer Ingelheim RCV, Vienna, Austria., Hinkel M; Boehringer Ingelheim RCV, Vienna, Austria., Lieb S; Boehringer Ingelheim RCV, Vienna, Austria., Jeschko A; Boehringer Ingelheim RCV, Vienna, Austria., Machado AA; Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Madensky T; Boehringer Ingelheim RCV, Vienna, Austria., Marszalek ED; Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Mahendra M; Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Melo-Zainzinger G; Boehringer Ingelheim RCV, Vienna, Austria., Molkentine JM; Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Jaeger PA; Boehringer Ingelheim RCV, Vienna, Austria., Peng DH; Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Schenk RL; Boehringer Ingelheim RCV, Vienna, Austria., Sorokin A; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Strauss S; Boehringer Ingelheim RCV, Vienna, Austria., Trapani F; Boehringer Ingelheim RCV, Vienna, Austria., Kopetz S; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Vellano CP; Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Petronczki M; Boehringer Ingelheim RCV, Vienna, Austria., Kraut N; Boehringer Ingelheim RCV, Vienna, Austria., Heffernan TP; Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Marszalek JR; Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Pearson M; Boehringer Ingelheim RCV, Vienna, Austria., Waizenegger IC; Boehringer Ingelheim RCV, Vienna, Austria., Hofmann MH; Boehringer Ingelheim RCV, Vienna, Austria. marco.hofmann@boehringer-ingelheim.com.
Jazyk: angličtina
Zdroj: Nature cancer [Nat Cancer] 2024 Sep; Vol. 5 (9), pp. 1352-1370. Date of Electronic Publication: 2024 Aug 05.
DOI: 10.1038/s43018-024-00800-6
Abstrakt: Combination approaches are needed to strengthen and extend the clinical response to KRAS G12C inhibitors (KRAS G12C i). Here, we assessed the antitumor responses of KRAS G12C mutant lung and colorectal cancer models to combination treatment with a SOS1 inhibitor (SOS1i), BI-3406, plus the KRAS G12C inhibitor, adagrasib. We found that responses to BI-3406 plus adagrasib were stronger than to adagrasib alone, comparable to adagrasib with SHP2 (SHP2i) or EGFR inhibitors and correlated with stronger suppression of RAS-MAPK signaling. BI-3406 plus adagrasib treatment also delayed the emergence of acquired resistance and elicited antitumor responses from adagrasib-resistant models. Resistance to KRAS G12C i seemed to be driven by upregulation of MRAS activity, which both SOS1i and SHP2i were found to potently inhibit. Knockdown of SHOC2, a MRAS complex partner, partially restored response to KRAS G12C i treatment. These results suggest KRAS G12C plus SOS1i to be a promising strategy for treating both KRAS G12C i naive and relapsed KRAS G12C -mutant tumors.
(© 2024. The Author(s).)
Databáze: MEDLINE
Externí odkaz: